Abstract

Fatigue is a common and major symptom in multiple sclerosis (MS). A number of potential mechanisms exist as to the cause of MS-fatigue. These include that it is an immune-mediated symptom or that it is due to neuroendocrine or autonomic dysfunction. Studies have shown reduced activity in cortical and deep grey matter regions and disruption of cortico-subcortical circuits has been theorised. This may lead to difficulty in the planning or pre-movement stage of activity with compensatory overactivity contributing to fatigue. Finally, dysfunction of the hypocretin system, deficiency of which occurs in narcolepsy, has also been suggested. A number of deep grey matter structures, including the basal ganglia, thalamus and hypothalamus, are implicated in these mechanisms and the work presented in this thesis explores their role.

Conventional magnetic resonance imaging (MRI) techniques whilst crucial in diagnosis and monitoring disease activity are generally felt to correlate poorly with disability and symptomatology. Quantitative MRI techniques have been shown to provide a more comprehensive evaluation of the extent of MS pathology and correlate better with clinical deficit. Tl relaxation time measurement is one such quantitative MRI technique and has been shown to demonstrate abnormalities in small structures such as the pyramidal tracts and correlate with disability.

Firstly, we measured the T1 relaxation times of the thalamus and basal ganglia in a cohort of MS patients and assessed for any relationship with fatigue severity. Secondly, in view of its key role in the autonomic, neuroendocrine and hypocretin pathways, we performed the same measurement in the hypothalamus of a cohort of patients and again assessed for any relationship to fatigue.

Subsequently, to further evaluate any possible contribution from the hypocretin system we measured cerebrospinal fluid (CSF) hypocretin-1 levels in patients with a number of neurological diseases including a cohort of MS patients and evaluated for any relationship with severity of self-reported fatigue and hypersomnolence.

Studies in MS-fatigue, including those undertaken by our group, traditionally rely on self-reported measures of fatigue severity. These questionnaire-based measures are subject to a number of drawbacks including rater bias and lack of definition of fatigue. In the final study, we assessed the effectiveness of the wakefulness-promoting drug, modafinil, in MS patients with and without fatigue by assessing its effect on objective measures of alertness and vigilance, including neurophysiological and laboratory-based measures. In addition, in this study we evaluated any potential role of the autonomic system in MS-fatigue.

We found significantly higher T1 relaxation times in a number of deep grey matter structures including the thalamus, putamen and latterly the hypothalamus in MS patients as compared to controls. The T1 relaxation time of the thalamus was higher in fatigued patients as compared to non-fatigued patients and it correlated with fatigue severity.

We found lower CSF hypocretin-1 levels in patients with MS and inflammatory disorders as compared to non-inflammatory conditions and this was significant in the inflammatory cohort. However, we found no relationship with fatigue or hypersomnolence severity. We did, however, detect a significant difference on a sympathetic cardiovascular reflex test between fatigued and non-fatigued patients. Finally we noted a significant improvement with modafinil, as compared to placebo, in a number of objective measures of alertness in patients with MS-fatigue and notably this was not a class-effect.

To this extent, the findings from this thesis provide evidence for the potential involvement of pathology in the thalamus in the mechanism of MS-fatigue, possibly through disruption of cortico-subcortical circuits. In addition, in a separate cohort of patients there was evidence of a relationship between autonomic disturbance and fatigue. We have however found no evidence of a relationship between the hypocretin system and fatigue in MS. Finally we have demonstrated supportive evidence for a role for modafinil in the treatment of fatigue, a symptom for which, despite its frequency and severity, there is often a paucity of treatment options available for MS specialists.